Browsing by Subject "Fludarabine"

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    Improving hematopoietic cell transplantation therapeutics:emphasis in pharmacokinetic-pharmacodynamic relationships and pharmacogenomics.
    (2009-12) Long-Boyle, Janel Renee
    Treatment-related mortality and acute graft vs host disease remain prominent clinical problems in nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Hence, the need for improved preparative regimens and immunosuppressive strategies in HCT persists. The research presented in my dissertation will be focused on defining pharmacokinetic-pharmacodynamic relationships, and pharmacogenomics involving two antineoplastic agents, fludarabine and clofarabine, and the immunosuppressive agent, mycophenolate all of which are used in the setting of HCT. Fludarabine is a purine analog commonly used in both adult and pediatric nonmyeloablative allogeneic HCT. Although the pharmacokinetics of fludarabine have been extensively studied in a variety of malignant diseases, very little data is available in nonmyeloablative HCT and the relationship between fludarabine pharmacokinetic parameters and clinical outcomes such as treatment-related mortality have yet to be evaluated. Similarly, no PK data is available for clofarabine; a newer purine analog currently used pediatric patients undergoing HCT for non-hematologic malignancies. Finally, mycophenolic acid pharmacokinetics in HCT recipients displays wide inter- and intra-patient variability in plasma concentrations and low mycophenolate exposure is associated with lower rates of engraftment and greater risk of acute graft vs host disease. Patient characteristics such as weight or body surface area, or clinical markers for hepatic and renal function incompletely explain pharmacokinetic variability suggesting there may be genetic factors influencing mycophenolate metabolism or transport. The methodologies and techniques employed to evaluate each individual agent will differ, including pharmacokinetic and statistical analyses. However, all projects share the common goal of improving patient outcomes and reducing toxicity in this very complex patient population.
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    Pharmacokinetics, pharmacodynamics, and dose optimization of fludarabine in nonmyeloablative hematopoietic stem cell transplantation.
    (2010-10) Baron, Kyle Thomas
    The first goal of this research was to develop models describing pharmacokinetics and pharmacodynamics of fludarabine in a patient population undergoing nonmyeloablative hematopoietic stem cell transplantation. The second goal was to leverage model information to identify fludarabine doses that are most likely to achieve optimal outcomes after transplant. Datasets consisting of intensively sampled F-ara-A plasma concentrations after approximately 40 mg/m2 fludarabine as well as outcome data (treatment-related mortality, maximum acute graft-versus-host disease grade, and neutrophil engraftment) were available at the start of the modeling work. Population pharmacokinetic models were built using NONMEM. Covariate models for pharmacokinetic parameters were derived, including a model for the typical value of clearance in the population as a function of weight, creatinine clearance, and comorbidity score. Bayesian generalized linear models linking F-ara-A exposure to outcome probabilities were fit using OpenBUGS software. Both models were evaluated using predictive model checking methods. Fludarabine doses were optimized with respect to individual outcomes by finding the posterior probability that a certain dose would meet specific criteria defining treatment "success". Doses were optimized simultaneously across all three outcomes using a utility index defined as the product of the individual outcome success probabilities. In general, the results recommend a reduction of fludarabine doses to optimize outcomes after hematopoietic stem cell transplantation.